The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyol.RTM., NSC 296961, and WR-2721 and which will hereinafter be referred to as "amifostine") and other aminoalkyl dihydrogen phosphorothioates are disclosed in U.S. Pat. No. 3,892,824 to Piper et al. This patent also discloses the known process for making a crystalline form of amifostine drug substance and is incorporated herein by reference. This crystalline form of amifostine has been shown to be relatively stable at room temperature for several years as well as at 50.degree. C. for several months. These compounds were originally developed as antiradiation agents (radioprotectants), in particular to be used against x-ray or nuclear radiation which may be encountered during military conflicts.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant i.e., as a protectant for the undesirable adverse effects which arise during the use of radiation therapy in the treatment of cancer and the use of chemotherapeutic agents, for example, alkylating agents such as cyclophosphamide, cisplatin, carboplatin, doxorubicin and its derivatives, and mitomycin and its derivatives. Similarly, it has been reported that amifostine has been used experimentally to protect HIV infected patients (AIDS) from the harmful side effects of 3'-azido-3'-deoxythymidine (AZT) therapy. Amifostine and its derivatives exert their protective effects without significantly affecting the beneficial properties of the administered therapeutic agents. This is in part due to the selective uptake of the protective thiol into normal tissue.
As used herein, the term "amifostine drug substance" refers to its pre-vacuum dried or pre-vacuum dried state which is available on an "as is" basis in a trihydrate form. Currently available sterile, vacuum dried formulations of amifostine drug product will be referred to as "amorphous amifostine", whereas the form covered by the present invention will be referred to as "crystalline amifostine" in order to distinguish between the two forms. Unless otherwise specified, quantities reported herein shall be calculated on an anhydrous basis.
Although amifostine has many advantageous properties, extensive difficulty has been encountered in trying to obtain a convenient, stable, sterile dosage formulation.
The present manner of manufacturing and packaging amifostine comprises the steps of filling into pre-sterlized vials a sterilized water solution comprising amifostine to a predetermined volume, cooling the vials and their contents, and removing the solvent by lyophilization to produce dried amifostine of a predetermined amount in each vial. [See L. Lachman, et al. The Theory and Practice of Industrial Pharmacy p 62-63, 1986]. This avoids substantial practical problems related to the packaging of bulk, solid amifostine using the so-called "dry filling" or "powder filling" method. Such problems include the difficulty in the manual manipulation of powders, the need to mill the powders to acceptable particle size and flowability, difficulty in maintaining particle-free, aseptic conditions, and the difficulty in supplying the precise dosage of solid amifostine into each vial.
However, the currently available formulation of amifostine. This amorphous form that is produced by lyophilization is thermally unstable. As a result, this lyophilized formulation must be maintained at temperatures at about -20.degree. C. and shipped at temperatures at about -70.degree. C. to about -20.degree. C. to avoid degradation of the formulated product. The need for low temperature during shipping and storage is an obstacle and shortcoming of currently available vacuum dried forms of amifostine. Special packaging and significant expenses are involved in the shipping and storage of the product. Moreover, hospitals without freezer storage conditions will be unable to supply amifostine for use to their patients (e.g., third world markets would be extensively hindered from using amifostine). However, since no alternative formulations were available, clinical trials were conducted using this formulation.
Hence, there is a need to develop a dosage form which has sufficient stability to provide a long shelf life at room temperature or under less stringent refrigeration, which is not uncommon for many drug products.
The present invention describes new and novel procedures which produce solid compositions containing vacuum dried amifostine, with and without pharmaceutically acceptable excipients such as mannitol, which have improved stability over the previously available composition.